Synaptically-released zinc has toxic impact in seizure, ischemia, and trauma, contributing to neuronal injury in all three conditions. Conversely, blockade of the excitotoxic synaptic zinc flux with zinc chelators can reduce neuronal degeneration markers by as much as 80%. We have recently discovered evidence indicating that Nitric Oxide (NO) may control the synaptic release of zinc. Should NO prove to be the controlling factor, this would open completely new avenues for management of zinc-induced brain damage in stroke, ischemia, trauma, and seizure. Moreover, prophylactic control of the Zn2+ toxicity via NO modulation could be used as therapeutic pretreatment in cardiac bypass and carotid endarterectomy procedures. Our pilot data indicate that NO infused into the brain simultaneously depletes presynaptic boutons of their zinc while releasing zinc into dialysates, and we have complementary data from brain slice preparations indicating that NO causes the release of Zn2+ into the bath. Perhaps more compelling, additional data suggest that zinc-induced neuronal injury after head trauma is decreased by up to 50% after blockade of NO* synthesis. The objective of the present proposal is to establish with certainty whether, in fact, NO controls Zn2+ release during excitotoxicity.